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A European perspective of globalCMC innovation

FDA/PQRI – Rockville, MD – April 10, 2019

Univ.-Prof. Dr. Sven Stegemann, Technische UniversitätGraz

Table of content

Introduction

A holistic view on drug therapy

Regulatory framework

CMC considerations for patient-centric drug product design

Case studies

The patient centric drug development dilemma

Conclusion

STE – FDA/PQRI Conference – April 10, 2019

Introduction Burden of disease and disease prevalence over life span in developed countries.

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cardiovascular

cancer

Respir.

mental

HIV

diabetes

Neo

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cardiovascular

cancer

Respir.mental

HIV

DALYs (disability-adjusted life years)across the life span

DALYs express thenumber of years lostdue to ill-health,disability or earlydeath.

DALY = YLL + YLD

Years of life lost (YLL)plus Years lost due todisability (YLD)

Murray et al Lancet 2012

Male Female


Introduction

Multimorbidity per age and socio-economic status and the relationship to prevalence ofphysical and mental disorders

Multimorbidity and socio-economic status by age Multimorbidity related physical and mental disorders by socio-economic status

Barnett et al Lancet 2012STE – FDA/PQRI Conference – April 10, 2019

Introduction

Increasing evidence for typicaldisease and co-morbidity clustersforming distinct patient populations

Pheno- and genotyping evolvethrough deep digital data analysis,iPSC and other emergingtechnologies

Barnett et al Lancet 2012

EMBO Mol Med (2017) 9: 1742–1762


A holistic view on drug therapyDefinition of health Medical: Absence of diagnosable deviations from the average population

Personal: Absence of symptoms perceived as threatening or debiliating

Society: Absence of behaviors outside the accepted norms

WHO: „Health is a state of complete physical, mental and social well-being and not merely theabsence of disease or infirmity.”

Goals and objectives

Medical: Prevent premature death and prolong life time

Personal: Well-being, independence, functional capacity and quality of life

Society: Organize and manage healthcare resources by ROI decisions



In 2000, 44,000 to 98,000 deaths occur yearly dueto 62 medical errors, making medical errors theeighth leading cause of death in the USA [1]

Therapeutic Failures and adverse drug withdrawalevents involving 54 drugs were associated 5.9%of hospitalizations; of these admissions, 90.0%were rated as potentially preventable mostly dueto medication nonadherence and suboptimalprescribing.[2]

Secondary non-adherence ranges from ~25 % ingastrointestinal disease to ~80 % oncology [3]

Gap between efficacy and effectiveness or therandomized clinical setting and the real world [4]

[1] American Hospital Association. Hospital Statistics. Chicago. 1999.[2] Marcum et al (2012) J Gerontol A Biol Sci Med Sci. 67(8):867–874[3] Gapgemini Report: Estimated annual pharmaceutical revenue loss due to medication non-adherence (2012)[4] Eichler et al Nature Rev Drug Discov 10:495 – 506 (2011)STE – FDA/PQRI Conference – April 10, 2019


Understand the patient journey

Stegemann Int J Pharm 2016STE – FDA/PQRI Conference – April 10, 2019

A holistic view on drug therapyWhat is progressing in healthcare and its provision Physicians progress into shared decision making Wearable diagnostics and digital health Organisation of lay persons in the internet (information

access) Patient involvement in technology design


A holistic view on drug therapyWhat is progressing in healthcare and its provision Physicians progress into shared decision making Wearable diagnostics and digital health Organisation of lay persons in the internet (information

access) Patient involvement in technolgy design

Patients are increasingly recognized as oneof the most important factors in achieving thetherapeutic outcomes as they are „in control“

of the last step

and

getting more and more empowered byeducation and information accessability.


A holistic view on drug therapy – Expectation to treatment model1. Acceptance of the disease

2. Patient expectation Effect bodily sensation/symptomes Compatibility with health believes Product perception and experience

3. Implementation plan

4. Reappraisal

5. Illusion of control

Stegemann S In: Developing drug products in an aging society, pp 153-170 (2016)STE – FDA/PQRI Conference – April 10, 2019


• The patient is the „owner“ of thedisease and therapy and carries allthe burden and outcomes

• The experience and perception ofthe disease and the treatment is asum of many factors of which theexperience and expectations arekey

• Patient centricity starts with thepatient and patient research

Healthcare system

Relatives/friendsSociety/status

Cultur/education

environment

Patient

Medicine

Disease

Stegemann In: Developing drug products in an Aging Society: from concept to prescribing pp 191-216 (2016)STE – FDA/PQRI Conference – April 10, 2019


Increasing focus on Real World Evidence (RWE) and Real World Data (RWD) Patient involvement in drug development and

the regulatory decision process Broader definition of „Quality“ beyond the

technical and chemical „intended use“ as one endpoint „special populations“ with regard to their needs Consideration of the aging process and

potential undiagnosed physiological changes


Regulatory frameworkUndiagnosed physiological changes: e.g. kidney function between older individuals

Chronic KidneyDisease (CKD) isdefined as eGFRFAS<60 mLmin/ 1.73 m2

and/or analbumin/creatinineratio >30 mg/g

In the BASE II Study25 % had CKD ofwhich only 1 % wasaware of

CKD in the BASE II population. 25 %CKD, of which 1 % was aware of.Kidney function dependend the

age. Different diagnosticmethods

König et al Gerontol 63:201-9 (2017)STE – FDA/PQRI Conference – April 10, 2019


Reflection Paper & Practice Guides

Reflection paper: Formulations of choice for the paediatric population (2006)

EMA Geriatric Medicines Strategy (2011)

Outcome report on pilot phase for participation of patient representatives in Scientific Advisory Group(SAG) meetings (2011)

Position paper on potential medication errors in the context of benefit-risk balance and risk minimisationmeasures (2013)

Points to consider for baseline characterisation of frailty status (2015)

Good practice guide on risk minimisation and prevention of medication errors (2015)

Reflection paper on the use of extrapolation in the development of medicines for paediatrics (2017)

Reflection paper on the pharmaceutical development of medicines for use in the older population (2017)

Reflection paper on physical frailty: instruments for baseline characterisation of older populations inclinical trials (2018)


Regulatory frameworkGuidelines ICH Q8 (R2) guideline on pharmaceutical development (2009)

quality defined as the suitability drug substance/product for intended use “in all cases, the product should be designed to meet patients’ needs and intended product

performance” ICH Topic E7 Studies in Support of Special Populations: Geriatrics (2009) EMA The role of patients as members of the EMA Human Scientific Committees (2011) Pharmacovigilance Module VI (2012)

This includes adverse reactions which arise from: “the use outside the terms of the marketing authorisation, including overdose, off-label use,

misuse, abuse and medication errors” EMA Guideline on pharmaceutical development of medicines for paediatric use (2013) Addendum to ICH 11: Clinical investigation of medicinal products in the paediatric population (2017) EMA Guideline on good pharmacovigilance practices (GVP) Product- or Population-Specific

Considerations IV: Paediatric population (2018)


CMC considerations for patient-centric drug products

Pharmaceutical drug product

The comprehensive presentation of the therapeutic entity to the end user (patient/caregiver/health care provider) including the type of dosage form; formulation; dose; dosingfrequency; primary, secondary, and tertiary packaging; medical device; dosing devices;instructions for use (as in the SmPC/PIL/ product label); and other authority-approvedpatient support tools and programs.

Patient centric pharmaceutical drug product design

The process of identifying the comprehensive needs of individuals or the target patientpopulation and utilizing the identified needs to design pharmaceutical drug products thatprovide the best overall benefit to risk profile for that target patient population over theintended duration of treatment.

Stegemann et al AAPS J 18(5):1047-55 (2016)STE – FDA/PQRI Conference – April 10, 2019


(Quality) Target Product Profil ((Q)TPP)

Forms the basis for product development considering product related characteristics: Intended use in clinical setting, route of administration, dosage form, delivery systems, dosage

strength(s), container closure system etc Therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics

(e.g., dissolution, aerodynamic performance) appropriate to the drug product dosage form beingdeveloped

Drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for theintended marketed product.

..and considering patient related characteristics: Individual physiology related factors (e.g. ADME, disease, drug-disease, drug-drug & age related

changes) Personality related (e.g. psychological situation, cognitive capacity, health literacy) physical functioning related (e.g. dexterity, sensory, motoric changes)



Patient-centric pharmaceutical drug product design elements Divided into:

Design Drivers (Characteristics disease/condition, Characteristics drug substance/ physiology,characteritistics drug therapy, characteristics drug product, patient characteritics, medicationmanagement (adherence and administration), Usability (handling, storage and disposal)

Design inputs (e.g. specific needs tobe considered) Design outputs (e.g. design option to address such needs)

Stegemann et al AAPS J 18(5):1047-55 (2016)STE – FDA/PQRI Conference – April 10, 2019


The non-obvious product-patient interface

Visual examination

Tactile sense

Usage-handling

Color Gloss Weight Material Task information

Temperature Rigidity/hardness Roughness/friction Weight Noise

Task response Resistance/strength Open-ability Task outcome Time for task Dosage form



Sensation

Perception

Cognition

Activate cells,receive signals

Memory

Movement

Interpret signals andstimuli

Translate, elaborateinto information

Recall, compareinformation

Physical response




Sensation*

Perception*

Cognition*

Memory*

Movement*

e.g. product identification error

e.g. product scheduling error

e.g. product manipulation error

e.g. product handling/use error




24

„In general, older people are the majority users ofmany medicines and at highest risk of encounteringpractical medication (useability) problems, which mayincrease the risk for poor adherence, medication errorsand/or reduced patient or care givers quality of life.“

„The Reflection Paper applies to any new applicationfor a marketing authorization (MA) or variation to enexisting MA , and for all application types including fulland abridged MAs (i.e. new medicinal products,generics, well established use).“

„They may also be of relevance for other age groupssuffering from similar impairments and/or needs (e.g. Aneasy to open packaging is relevant for rheumaticpatients of eny age). They need to be considered in apatient centric approach to pharmaceutucaldervelopment.“


CMC considerations for patient-centric drug products• Patient acceptability defined as ability and willingness of the patient to self administer (or

lay or professional care giver)

• The different route of administration, the pro‘s and con‘s of preparations For oral use (swallowing, not to swallow)

Different preparation for ear and eye

Nasal and pulmonary delivery

Cutaneous and transdermal

Rectal, vaginal and urethral dosage forms

Parenteral administration froms

• Administration through enteral feeding tubes

• Modifications of dosage forms Co-administration or mixing with food or beverages

Tablet splittingSTE – FDA/PQRI Conference – April 10, 2019


• Dosing frequence

• Excipients in the formulation

• Container and closure systems Ease of opening Multi-compartment compliance aids,

Multi Dose Dispening systems

• Devices and technologies

• Medicinal and product information

• Medication management Multiple medication use & polypharmacy Medication recognition Switching between medicines



„As knowledge on testing a product‘s patientacceptability in the older population is fragmented,the selection of the method and acceptance criteriais left to the company. However, companies willneed to justify their approach with respect to theproduct benefit to risk considerations in the olderpopulation, including the risk of poor adherernceand/or alternative administration strategies.“

„The aspects associated with older age may alsobe of relevance to adults of middle or youngerage as well as children (e.g. juvenile idiopathicarthritis). Therefore, a patient centric approach tothe medicine‘s pharmaceutical development isencouraged.“



• Motoric• Sensoric• Cognition• Visual• Hearing• Saliva• Taste• Psychological

• Pharmacokinetic &Pharmacodynamicchanges

• Multimorbidity• Vulnerability• Polypharmacy• Frailty-Syndrom• Homeostasis

Targetedpatientprofile

Patient characteristics Patient perception

• The critical personality„Each pill is one too much“

• The organized personality„I take my tablets regularely,

independent from the circumstances.“

• The helpless personality„This should be decided by the doctor, I

don‘t have a clue on it.“

• The routine personality„I am used to it. The idea to not takeanything – I would be concerned.“



Patient-centric pharmaceutical drug product design

29

Product-related characteristics Patient-related characteristics

Design Drivers Design Inputs Design Outputs

Targeted Product (and Patient) Profile

QbD - ICH Q8 (R2): In all cases, the product should be designed to meet patients’ needs andthe intended product performance.

Stegemann et al AAPS J 18(5):1047-55 (2016)

Conceptualization – design phase – interative design testing

Lead design testing and final design confirmation in targeted patients


Case studies

For the rheumatoid arthritis (RA) compound certolizumab pegol, UCB developed an ergonomicallydesign self-injection syringe and performed comparative testingwith 22 RA patients and several endpoints

User perception

Grip strength and force exertion profile during injection

Sheikhzadeh A, Appl Ergon. 2012;43:368-375

Simulated skin pad placed on their thigh to mimic the injection

Case studies

Comparative study in RA patients with theexisting syringe ® and ergonomic designsyringe (N)

Higher acceptability of the new syringe

Patients were able to exert higher forces onthe plunger during administration

Sheikhzadeh A, Appl Ergon. 2012;43:368-375

Case studies

The features of the ergonomically designed self-injection syringe for the treatment ofrheumatoid arthritis

Case studies

The BAGSO Working Group on Patient Information leaflet Together with the various stakeholders, the BAGSO working group developed guidance for

the design of patient information leaflets

The 7 points that are consider important: Readable scripture and letter size Patient appropriate language Information about the disease and the effect of the drug product Structured, well arranged document presentation Use of pictures and pictograms Use of information and advice boxes Quoting additional support offers e.g. Self-help groups

It will remain most difficult to provide sufficient knowledge on health-disease

Recommendations from BAGSO

The patient centric product development dilemma

The mismatch with the existing business model and mind set

Science &technology driven

Manufacturing &supply chain Quality of Life

Human nature &psychosocial driven

Instruction Behavior

Pharm Sci PatientsBetween scientific excellence and patients life expertise

Randomized &controlled clinical trail

Quality, safety &efficacy

CoA, stability

Effectiveness

Usability &acceptability

Expectation

1998 2001STE – FDA/PQRI Conference – April 10, 2019

Conclusion

Patients are being recognized as a major factor in achieving therapeutic outcomes in the realworld settings (effectiveness)

Patients are getting more involved in their health and healthcare decision by ease ofinformation access and lay-person organization in the internet (eroding the white coatauthority)

The pharmaceutical product is beyond simple “health repair”, it is the patient experience withthe disease (disease burden), the treatment (therapeutic burden) and the expectation in thepersonal outcomes

Multimorbidity is associated with cumulative complexity (polypharmacy) and declining patientcapability (functional impairment and disability)

The benefit to risk might change with age (life expectancy, severity of ADR) and multimorbidity(drug – drug, drug – disease interactions)

Multidisciplinary collaborations are required to understand patient behavior and intuitive use ofmedicines including learnings from the consumer industry


Conclusion

VanMoof reduced transport damages from Europe to the USA by 80 %using a simple visual trick: The perception of a sensitive TV screen inside!

Building on intuition – dealing with transport damage


Conclusion

Fashion & its tissue is very sensitive to thewashing conditions

Yet, we manage many different types of clotheswithout issues, because… … we agreed globally on pictograms


Univ.-Prof. Dr. Sven StegemannGraz University of TechnologyInffeldgasse 138010 GrazAustriae-mail: [email protected]: +43 316 873 0422Mobile: +49 172 6054869Fax: +43 (316) 873 - 1030422


a european perspective of global cmc innovation...cmc innovation fda/pqri – rockville, md –...

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